Cri Du Chat Syndrome

Introduction

Cri-du-chat is a genetic disorder that is caused by a deletion of the short arm of chromosome 5. The name of the syndrome, meaning cat cry was coined after the main clinical finding of a high-pitched, monochromatic cat-like cry. The clinical picture, severity, and progression of the disease vary depending on the region of the chromosome that is deleted and whether it is terminal or interstitial. In other words, differences in phenotype can be attributed to the differences in genotype. This disorder is often characterized by distinctive facial features, delayed development, and intellectual disability. [1],[2]

Etiology

Cri-du chat is caused by either a partial or complete deletion of chromosome 5p. Most of the deletions occur de novo. The deletions occur as random events during the formation of reproductive cells in early fetal development. Around 80% to 90% are paternal in origin, which can arise from a chromosomal breakage during gamete formation. The remaining 10% to 15% are a result of unbalanced parental translocation. Moreover, 80% to 90% of cases result from terminal deletions of chromosome 5 while 3% to 5% are due to an interstitial deletion. Mosaicism, inversions, and ring chromosomes are less common mechanisms.[2]

Epidemiology

Although cri du chat is considered a rare disorder, it is one of the most common chromosomal anomalies. The incidence ranges from 1:15,000 to 1:50,000 liveborn infants. The incidence in females is slightly higher than males. The exact incidence and prevalence worldwide and among races has not been established. Similarly, specific risk factors associated with prenatal events or parental age have not been established. However, there are occasional reports of parental exposure to radiation, hyperemesis, anorexia, and toxemia.[3]

Pathophysiology

Patients demonstrate phenotypic and genotypic variability. A partial deletion of the short arm of chromosome 5 has been found to be the cause for the characteristic phenotype. The phenotype being identifiable in spite of variations in deletion size has led to a theory that a critical region is responsible for the characteristic feature in hemizygosity. The region identified is 5p15.2, and individuals with a deletion of chromosome 5 that do not include this region do not show a typical phenotype and, in some cases, are even normal.

Cytogenetic studies have helped identify two regions, 5p15.3, which is responsible for the characteristic cry, and 5p15.2 which is responsible for the other major clinical findings. Similarly, other regions have been identified for other features such as speech retardation and dysmorphism. Therefore, the clinical manifestations depend on the deletion of the critical region. Another important factor for the manifestation is the size as well as the type of deletion and whether it is interstitial or terminal.

The most characteristic feature of this disease is high-pitched crying, and the pathogenesis can be attributed to the anatomical alteration of the laryngeal morphology which may be a result of:

A small, floppy epiglottis

Hypoplasia of the larynx

A narrow or diamond-shaped larynx

Abnormal airspace in the posterior area during phonation

However, not all patients with abnormal crying have the above features. Therefore, there may be neurological changes as well.[3]

History and Physical

Neonatal Period

In the neonatal period, the most characteristic finding is a high-pitched, monotonous cry, which normally disappears within the first few months of life. The cry is not limited to this syndrome alone and has been reported in a few other neurological disorders. Newborns also exhibit low birthweight and microcephaly as well as asphyxia, muscle hypotonia, and impaired suction. These lead to impaired growth and development during the first few years of life. Recurrent respiratory, as well as intestinal infections, have been reported. [3]

General characteristics:

(a) Craniofacial malformations:

Microcephaly

Moon face

Hypertelorism

Prominent epicanthal folds

Large nasal bridge

Downturned corners of the mouth

Short philtrum

Premature gray hair

Abnormal transverse flexion creases

Uncommonly:

Downward slanting palpebral fissures

Low-set ears

Narrow auditory ducts

Preauricular tags

Deafness

Myopia and cataracts

Hypersensitivity of pupils to methacholine

Hypospadias and cryptorchidism

With increasing age, the following features change:

Hypotonia in neonatal period is replaced with hypertonia

Prominent microcephaly

Prominent supraorbital arch

Dental malocclusions

Moon face changes into a more narrow vertical face in adulthood

(b) Other anomalies that might be present:

Hypersensitivity to sound

Cardiac disorders including congenital heart defects

Cutaneous hemangioma

Renal pathology

(c) Orofacial abnormalities:

High palate

Mandibular microretrognathia

Hypoplasia of the enamel

Chronic periodontitis

(d) Developmental and behavioral manifestations:

Hyperactivity

Self-injurious behavior

Repetitive movements

Gentle personality

Obsessive attachment to objects

Comprehension of speech is better than their ability to express or communicate [2]

Evaluation

Antenatally

Cri du chat can be diagnosed with amniocentesis during the antenatal period where deletion of chromosome 5 will be seen. The structural abnormalities can be observed sonographically. Also, fetuses who show mosaicism may display fetoplacental and fetoamniotic chromosomal abnormalities along with microcephaly and cerebellar hypoplasia. [3][4][5][6][3]

Postnatally

A diagnosis can be made based on clinical findings. The occurrence of certain characteristic findings such as microcephaly, low birthweight, moon face, muscle hypotonia, and a cat-like cry together should raise clinical suspicion of the condition. Sometimes this can be difficult because the features may not be obvious as patients show a cytogenetic variation leading to phenotypic variation. The clinical features, as well as the severity and prognosis, can be determined by the size and position of the deletion.

If clinical suspicion is present, one of the first tests that can confirm the diagnosis is a karyotype analysis. However, in cases where the clinical suspicion is high in the presence of a normal karyotype further specific tests can be carried out such as FISH (fluorescence in-situ hybridization), CGH (comparative genomic hybridization), or quantitative PCR (polymerase chain reaction).

FISH has led to an improvement in the diagnosis of genetic disorders caused by chromosome deletion and has provided a phenotypic map and the associated genome of an individual. Newer techniques, such as CGH, has opened up new doors by including the whole genome and the associated markers which can identify genetic alterations.

There have been very few studies on the MRI findings. However, pontine hypoplasia seems to be the most common feature. This is associated with other findings such as cerebellar hypoplasia and microcephaly as well as corpus callosum anomalies. Supratentorial abnormalities also have been observed. [2]

Treatment / Management

There is no specific treatment for patients due to the early onset of cerebral damage during embryonal development. However, patients benefit from rehabilitation, especially when it is provided early. This has shown to improve prognosis as well as social adaptation.

During the neonatal period, physical therapy should be started in the first week of life to help with any difficulty in swallowing and suction. Breastfeeding is still possible, and intensive care is rarely necessary.[7][1][8]

Physical therapy, psychomotricity, and speech therapy are suggested for psychomotor and speech retardation. Patients often have sensorineural deafness; therefore, audiometric examinations should be carried out in all children. Other helpful treatments include surgery, special diet, and healthy routines.

Families should be involved in the care of the patient. They should be provided with information about the disease and available support groups.

Genetic counseling services should be offered for subsequent pregnancies.[3][9][3]

Prognosis

Morbidity and mortality rates decrease after the first few years of life. It is reported that 75% of deaths occur during the first month of life, and about 90% of deaths occur during the first year. It is important to note that the type, size, and location of the deletion(s) greatly influence the prognosis.

One of the most important factors in the prognosis of the disease is an early diagnosis. Early diagnosis allows for the implementation of therapeutic measures early on to improve the outcome of physical as well as psychomotor development and helps with social adaptation. [2]

Pearls and Other Issues

Cri-du-chat is a rare genetic disorder caused by deletion of the short arm of chromosome 5.

Differences in phenotype can be attributed to differences in genotype which also plays a role in the severity and prognosis.

The most characteristic finding is a high-pitched, monotonous cry. Other features include microcephaly, low birthweight, hypotonia, psychomotor retardation, and craniofacial malformations.

A clinical diagnosis can be made. However, a karyotype analysis can be done to confirm the diagnosis if clinical suspicion is high.

In the presence of a normal karyotype, and if the clinical suspicion is high, more specific cytogenetic studies can be carried out such as FISH or CGH.

Management revolves around physical therapy and rehabilitation programs as early as possible that will improve prognosis and social adaptation.

Morbidity and mortality are the highest in the first few years of life. Ninety percent of deaths occur in the first year.

Enhancing Healthcare Team Outcomes

Cri du chat is managed by an interprofessional team that includes, nurses, therapists, social workers and dietitians. There is no specific treatment for patients due to the early onset of cerebral damage during embryonal development. However, patients benefit from rehabilitation, especially when it is provided early. This has shown to improve prognosis as well as social adaptation. During the neonatal period, physical therapy should be started in the first week of life to help with any difficulty in swallowing and suction. Breastfeeding is still possible, and intensive care is rarely necessary.[7][1][8]

Unfortunately outcomes for infants with this disorder are poor. They face numerous difficulties with feeding, breathing and development. Most die within the first few months but those with mild deficits may live longer.